COVID-19–RELATED ADVERSE EVENTS IN THE PHASE 3 POETYK TRIALS OF THE ALLOSTERIC TYROSINE KINASE 2 INHIBITOR, DEUCRAVACITINIB, IN PATIENTS WITH MODERATE TO SEVERE PLAQUE PSORIASIS

BackgroundDeucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis. Deucravacitinib suppresses signaling of cytokines involved in the pathogenesis of immune-mediated diseases including psoriasis, psoriatic arthritis, and systemic lupus erythematosus. Deucravacitinib was efficacious compared with placebo in phase 2 trials in psoriatic arthritis and systemic lupus erythematosus.[1,2] In two phase 3 trials in patients with moderate to severe plaque psoriasis (POETYK PSO-1 [NCT03624127], PSO-2 [NCT03611751]), deucravacitinib showed superior efficacy versus placebo and apremilast.[3,4] Upon completion of either psoriasis trial, patients could enroll in the POETYK long-term extension (LTE) trial (NCT04036435).ObjectivesTo evaluate the incidence rate and severity of adverse events (AEs) due to COVID-19 with deucravacitinib treatment in the POETYK PSO-1 and POETYK PSO-2 trials and open-label POETYK LTE trial.MethodsIn PSO-1 (N=666) and PSO-2 (N=1020), adult patients with moderate to severe plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily. At Week 16, placebo patients in both trials switched to deucravacitinib. Based on their Week 24 PASI response, apremilast patients continued with apremilast or switched to placebo or deucravacitinib. In PSO-1, patients randomized to deucravacitinib continued treatment for 52 weeks;in PSO-2, some patients randomized to deucravacitinib had a randomized treatment withdrawal period. At Week 52, patients could enroll in the open-label LTE and receive deucravacitinib. Incidence rates and severity of COVID-19–related AEs in the POETYK trials (n=1364;2076.7 person-years [PY] of follow-up) were compared with the Janssen/Johnson & Johnson COVID-19 vaccine trial placebo group (n=19,544;3096.1 PY of follow-up). This reference population was selected due to the study design and timing of the trial, which occurred when variants were in circulation.ResultsAs of October 1, 2021, 1519 patients received ≥1 dose of deucravacitinib over a 2-year follow-up period;1364 patients met criteria for this analysis, with deucravacitinib exposure since the pandemic onset (estimated to be January 1, 2020). In total, 153 deucravacitinib patients reported a COVID-19–related AE, for an overall exposure-adjusted incidence rate (EAIR) of 7.4/100 PY (95% CI, 6.2–8.6). Serious COVID-19–related AEs occurred in 43 patients (EAIR, 2.1/100 PY;95% CI, 1.5–2.8), including 30 with COVID-19 and 13 with COVID-19 pneumonia;this rate was within the margins of those for moderate to severe COVID-19 reported in the reference population (EAIR, 16.5/100 PY;95% CI, 15.0–17.9). Deaths due to COVID-19 occurred in 6 patients (EAIR, 0.3/100 PY;95% CI, 0.1–0.6), with the COVID-19–related mortality rate being consistent with the reference population (EAIR, 0.23/100 PY;95% CI, 0.1–0.5). Treatment was discontinued due to COVID-19 or COVID-19 pneumonia in 7 patients, including the 6 patients who died due to COVID-19.ConclusionCOVID-19 was among the most frequently reported AEs during the 2-year period of the pooled PSO-1, PSO-2, and LTE trials due to the temporal overlap of the pandemic with the trials. However, COVID-19 infection and death rates did not differ from the reference population;most infections were not serious and did not lead to treatment discontinuation. Based on this analysis, deucravacitinib did not appear to increase the risk of COVID-19 nor its progression to severe outcomes.References[1]Mease PJ, et al. Ann Rheum Dis. 2022;81:815-822.[2]Morand E, et al. Arthritis Rheumatol. 2022;Nov 11 (Epub ahead of print).[3]Armstrong A, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02256-3.[4]Strober B, et al. J Am Acad Dermatol. 2022;S0190-9622(22)02643-3.AcknowledgementsThese clinical trials were sponsored by Bristol Myers Squibb.Disclosure of InterestsDiamant Thaçi Speakers bureau: AbbVie, Almirall, Amgen, Biogen Idec, Boeh inger Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Consultant of: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Grant/research support from: AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Galderma, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, Target Solution, and UCB, Kenneth B Gordon Consultant of: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, and Sun Pharma, Grant/research support from: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, and Sun Pharma, AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, and UCB, Melinda Gooderham Speakers bureau: Glenmark, Actelion, AbbVie, Galderma, Leo Pharma, Pfizer, and Regeneron, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Sanofi Genzyme, and Valeant, Consultant of: Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, Sanofi Genzyme, and Valeant, Andrew Alexis Speakers bureau: Pfizer, Regeneron, and Sanofi Genzyme, Consultant of: AbbVie, Allergan, Almirall, Amgen, Arcutis, AstraZeneca, Bausch Health, Beiersdorf, Bristol Myers Squibb, Dermavant, Galderma, Janssen, Leo Pharma, L'Oreal, Pfizer, Sanofi-Regeneron, Sol-Gel, UCB, Valeant, VisualDx, and Vyne, Grant/research support from: Almirall, Amgen, Arcutis, Bristol Myers Squibb, Cara, Galderma, Leo Pharma, Menlo, Novartis, and Valeant (Bausch Health), Varsha Lalchandani Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Julie Scotto Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Lauren Hippeli Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Matthew J Colombo Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Tamara Lezhava Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mark Lebwohl Consultant of: Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Arena, Aristea, Arrive Technologies, Avotres, BiomX, Boehringer Ingelheim, Brickell Biotech, Bristol Myers Squibb, Cara, Castle Biosciences, CorEvitas' (Corrona) Psoriasis Registry, Dermavant, Dr. Reddy's Laboratories, Evelo Biosciences, Evommune, Forte Biosciences, Helsinn Therapeutics, Hexima, Leo Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica, Grant/research support from: AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen, Ortho Dermatologics, Regeneron, and UCB.

The effect of ACE inhibitors and ARBs on outcomes in hospitalized patients with COVID-19.

BACKGROUND: Contradictory opinions exist regarding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in patients with hypertension, which is the most common comorbidity associated with COVID-19. Herein, the effects of ACEIs and ARBs on outcomes of COVID-19 patients were evaluated. METHODS: In this cross-sectional study, the outcomes of COVID-19 patients were compared between patients who received pretreatment ACEIs or ARBs and those who did not. RESULTS: The incidence of moderate and severe forms of COVID-19 was significantly higher in patients taking ACEI/ARB drugs (P-value = 0.012). Also, patients taking ACEI/ARB drugs (P-value = 0.034), patients with hypertension (P-value = 0.011), and patients with dyslipidemia (P-value = 0.011) experienced more severe forms of COVID-19. There was an association between increased length of hospital stay and dyslipidemia (P-value = 0.033) and the use of ACEI/ARB drugs (P-value = 0.041), while no correlation was found between other parameters in univariate linear regression analysis as well as multivariate linear regression. There was an association between increased mortality of patients with increasing age (P-value < 0.001), BMI greater than 30 kg/m2 (P-value = 0.02), asthma (P-value = 0.003), and dyslipidemia (P-value = 0.045). CONCLUSIONS: ACEI/ARB drugs put COVID-19 patients at high risk for moderate to severe forms of COVID-19 and higher length of hospital stay. Although, it is notable that these drugs did not significantly affect specific adverse outcomes of COVID-19, such as the need for admission to the intensive care unit (ICU), length of ICU stay, ventilation, and mortality.

Angioedema induced by angiotensin-converting enzyme inhibitors: An analysis of hospitalizations during the covid-19 pandemic.

BACKGROUND: The pathogenesis of angioedema induced by angiotensin-converting enzyme inhibitors is based on the accumulation of bradykinin as a result of angiotensin-converting enzyme blockade. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 receptor, which may inhibit its production and thereby lead to an increase in bradykinin levels. Thus, SARS-CoV-2 infection may be a likely trigger for the development of angioedema. AIMS: This study aimed to analyze cases of hospitalizations of patients with angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers during the coronavirus disease 2019 (COVID-19) pandemic. MATERIALS AND METHODS: This study retrospectively analyzed medical records of patients admitted to the Vitebsk Regional Clinical Hospital between May 2020 and December 2020 with isolated (without urticaria) angioedema while receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In all patients, smears from the naso and oropharynx for COVID-19 were analyzed by polymerase chain reaction. RESULT(S): Fifteen inpatients (9 men and 6 women) aged 44-72 years were admitted because of emergent events, of which 53.6% had isolated angioedema. In two cases, a concomitant diagnosis of mild COVID-19 infection was established with predominant symptoms of angioedema, including edema localized in the face, tongue, sublingual area, and soft palate. All patients had favorable disease outcomes. CONCLUSION(S): Patients with angiotensin-converting enzyme inhibitor-induced angioedema may require hospitalization to monitor upper respiratory tract patency. There were cases of a combination of angiotensin-converting enzyme inhibitor-induced angioedema and mild COVID-19. Issues requiring additional research include the effect of SARS- CoV-2 infection on the levels of bradykinin and its metabolites, the triggering role of COVID-19 in the development of angioedema in patients receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, recommendations for the management of patients with angiotensin-converting enzyme inhibitor-induced angioedema, and a positive result for COVID-19.Copyright © 2020 Pharmarus Print Media All rights reserved.

In-silico studies of active phytochemicals from siddha medicinal herbs of karisalai chooranam against SARS-CoV-2 main protease (3 CLpro), RNA dependent RNA polymerase and angiotensin-converting enzyme II receptor

Aim: The contagious disease COVID 19 is a recently out-broken pandemic situation which threatens humankind all over the world. Siddha system of medicine is one of the traditional medical systems of India, which has provided a novel remedy for many epidemics like Dengue, Chicken guinea earlier. On evaluating the literature evidence and considering the mortality and severity of the disease, we have attempted to identify the possible inhibition of viral replication by "Karisalai Chooranam" - a polyherbal Siddha formulation which contains herbs like Karisalai (Wedelia chinensis), Thoodhuvelai (Solanum trilobatum), Musumusukai (Melothria maderaspatana) and Seeragam (Cuminum cyminum). The aim of this study was to identify the bioactive components present in Karisalai chooranam and pin down the components that inhibit COVID 19 protease by In Silico molecular docking analysis. Material and methods: The study was performed for the active compounds present in the herbs (Wedelia chinensis - Benzoic acid, Solanum trilobatum- Disogenin, Melothria maderaspatana- beta-sitosterol, Cuminum cyminum L- Coumaric acid and Limonene) with three potential targets, PDB id: 6LU7 3-chymotrypsin-like protease (3CLpro), PDB id: 6-NUR RNA dependent RNA polymerase and PDB id: 2AJF Angiotensin-converting enzyme II (ACE2) receptor using Autodock Vina. Key findings: The active phytocomponents present in "Karisalai chooranam" was found to inhibit the target 3CL proenzyme and hereby halt the formation of 16 non-structural proteins (nsp1-nsp16) that are highly essential for viral replication and there by prevents viral survival in the host environment. The phytocomponents also inhibited the target RNA dependent RNA polymerase (PDB)-6NUR RdRp which possess versatile action in mediating nonstructural protein (nsp 12) essential for viral replication. A significant binding against the target Angiotensin-converting enzyme II (ACE2) receptors - PDB- 2AJF was found which was recognized as a binding site for novel coronavirus to cause its pathogenesis. Among the five active components present in the herb, the binding ability of Disogenin and beta-sitosterol with COVID19 protease suggests a possible mechanism of protease inhibition and thus preventing viral replication. Significance: The results strongly suggest that phytocomponents of "Karisalai chooranam" may act as a potential therapeutic agent for the management of COVID-19 and related symptoms. Further, the efficacy of the active compounds should be tested in vitro before being recommended as a drug.

Antiviral activitiy of curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

SARS-CoV-2 genome encodes two large polyproteins (pp), pp1a and pp1ab which are cleaved and transformed into a mature form by a protease, non-structural protein 3 (NSP3). NSP3 is encoded by open reading frame (ORF) 1a/b. Curcuma longa (C. longa) or turmeric has been documented to have antiviral effects. The aim of this study was to assess the viral activities of C. longa against SARS-CoV-2 focusing on its potency to inhibit viral replication by targeting NSP3. PubChem databases were used to obtain the metabolic profile of C. longa. The compound's interaction with nucleocapsid was analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score presents all compounds of C. longa have higher binding affinity than the native ligand with cyclocurcumin as the lowest score (-128.38 kcal/mol). This anti-viral activity was hypothesized from the similarity of hydrogen bonds with amino acid residues Ser 128 and Asn 40 as key residues present in Ribavirin. This study reveals that C. longa is the potential to be developed as an antiviral agent through replication inhibition in SARS-CoV-2 targeting its replication mediated by NSP3.

Discontinuation of Antihypertensive Drug Use Compared to Continuation in COVID-19 Patients: A Systematic Review with Meta-analysis and Trial Sequential Analysis.

INTRODUCTION: COVID-19 related mortality is about 2%, and it increases with comorbidities, like hypertension. Regarding management, there is debatable evidence about the benefits of continuation vs. discontinuation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB). AIM: We performed a systematic review to assess the effects and safety of in-hospital discontinuation compared to continuation of ACEI/ARB in COVID-19 patients. METHODS: We systematically searched on PubMed, Scopus, and EMBASE from inception to June 19, 2021. We included observational studies and trials that compared the effects and safety of continuing ACEI/ARB compared to discontinuing it in COVID-19 patients. Effects sizes for dichotomous variables were expressed as risk ratios (RR) and 95% confidence intervals. For continuous variables, effects were expressed as mean difference (MD). We used random effect models with the inverse variance method. We assessed certainty of evidence using the GRADE approach. RESULTS: We included three open-label randomized controlled trials and five cohort studies. We found that the continuation group had lower risk of death compared with the discontinuation group only in the cohort group (RR: 0.46, 95% CI: 0.24-0.90), but not in the RCT group (RR: 1.22, 95% CI: 0.75-2.00). The ICU admission rate was significantly lower in the continuation group (RR: 0.46, 95% CI: 0.31-0.68) in the cohort group, but not in RCT group (RR: 1.03, 95% CI: 0.67-1.59). We did not find significant differences between groups regarding hospitalization length, hypotension, AKI needing renal replacement therapy, mechanical ventilation, new or worsening heart failure, myocarditis, renal replacement therapy, arrhythmias, thromboembolic events and SOFA AUC. The GRADE approach revealed that the certainty ranged from moderate to high level. CONCLUSIONS: There is no significant difference in mortality and other outcomes between continuation and discontinuation groups.

In silico-based studies on phytochemicals from native Indian plants as potential inhibitors of SARS-CoV-2

This study aims to analyze the AntiCovid effect of Phytocompounds extracted from Native Indian Plant species by computational methods such as Molecular Docking. Through this study keeping the Indian Heritage alive we characterized the ability of these phytochemicals as inhibiting agents of the Main Protease enzyme of this Virus. The lack of any effective treatment and the reoccurrence of cases despite Vaccination necessitates the quick provision of anti-SARS-CoV-2 drugs. Natural substances are getting a lot of attention for SARS-CoV-2 therapy as they have proven antimicrobial activities and are a key source for numerous antiviral drugs. Despite the fact that this virus has several identified target receptors, Main Protease (Mpro) is crucial for viral replication. In this study, 26 phytochemicals from 10 native Indian plant species were studied. Our docking studies demonstrated that compounds Quercetin, Withaferin A, Sominone, and Nimbin were likely to be more favorable than the natural inhibitor N3, with binding energies of-8.42, -9.21, -9.95, and -8.88 kcal/mol, respectively. These four candidate natural compounds were further examined for their bioavailability scores through ADMET analysis to prove the safety of these compounds as well as their drug likeliness. Through the results it was indicated that these natural phytochemicals have a significant potential of inhibiting the SARS-CoV-2 Mpro enzyme and might be utilized to treat SARS-CoV-2 and manage public health, subject to in vitro validation in the future.

SARS-CoV-2 infection and smoking: What is the association? A brief review.

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

Evaluation of the Association between Multilobar Involvement and ACE Inhibitor Use in SARS-CoV-2 Patients

Aim: Angiotensin-converting enzyme 2 (ACE2) acts not only as an enzyme but also as a thought to be central receptor by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters host cells. Angiotensin-converting enzyme inhibitors (ACEIs) are thought to $1 are central to SARS-CoV-2 progression. However, its effect on clinical outcomes is still not fully explained. In this study, we investigated the effects of ACEIs use on pulmonary computed tomography findings. Method(s): The data of the patients who were hospitalized for SARS-CoV-2 pneumonia and were using medications for the diagnosis of hypertension from 20th March to 20th June 2020 were evaluated retrospectively. Patients were divided into 2 groups patients using ACEIs and not using ACEIs. Result(s): The study was conducted with 107 patients. Mild cases without signs of pneumonia were excluded from this study. Moderate cases were accepted as patients with symptoms related to the respiratory system and pneumonia detected on imaging. SpO2<=93%, >=30 breaths/min respiratory rate, and patients who developed respiratory failure, mechanical ventilator need, shock, or multiorgan failure were included in the severe and critically ill cases group. Severe and critical cases were evaluated as a single group. When the radiological images of the patients were examined, it was remarkable that multilobar findings were less common in the ACEIs using group (p<0.001). At the clinical end point, mortality rates in patients using ACEIs (12.7%) were significantly lower than patients without using ACEIs (32.7%). Conclusion(s): In our study, we showed that SARS-CoV-2 progresses with less multilobar involvement in pulmonary computed tomography in patients using ACEI.Copyright © 2023 by The Medical Bulletin of Istanbul Haseki Training and Research Hospital The Medical Bulletin of Haseki published by Galenos Yayinevi.

Enzyme Inhibitors from Gorgonians and Soft Corals.

For decades, gorgonians and soft corals have been considered promising sources of bioactive compounds, attracting the interest of scientists from different fields. As the most abundant bioactive compounds within these organisms, terpenoids, steroids, and alkaloids have received the highest coverage in the scientific literature. However, enzyme inhibitors, a functional class of bioactive compounds with high potential for industry and biomedicine, have received much less notoriety. Thus, we revised scientific literature (1974-2022) on the field of marine natural products searching for enzyme inhibitors isolated from these taxonomic groups. In this review, we present representative enzyme inhibitors from an enzymological perspective, highlighting, when available, data on specific targets, structures, potencies, mechanisms of inhibition, and physiological roles for these molecules. As most of the characterization studies for the new inhibitors remain incomplete, we also included a methodological section presenting a general strategy to face this goal by accomplishing STRENDA (Standards for Reporting Enzymology Data) project guidelines.

RAAS inhibitors are associated with a better chance of surviving of inpatients with Covid-19 without a diagnosis of diabetes mellitus, compared with similar patients who did not require antihypertensive therapy or were treated with other antihypertensives.

Purpose: The effect of renin-angiotensin-aldosterone system (RAAS) inhibitors in combination with COVID-19 and diabetes mellitus (DM) remains unknown. We assessed the risk of death in COVID-19 inpatients based on the presence or absence of DM, arterial hypertension (AH) and the use of RAAS inhibitors or other antihypertensives. Methods: The results of treatment of all adult PCR-confirmed COVID-19 inpatients (n = 1097, women 63.9%) from 02/12/2020 to 07/01/2022 are presented. The presence of DM at the time of admission and the category of antihypertensive drugs during hospital stay were noted. Leaving the hospital due to recovery or death was considered as a treatment outcome. Multivariable logistic regression analysis was used to assess the risk of death. Patients with COVID-19 without AH were considered the reference group. Results: DM was known in 150 of 1,097 patients with COVID-19 (13.7%). Mortality among DM inpatients was higher: 20.0% vs. 12.4% respectively (p=0.014). Male gender, age, fasting plasma glucose (FPG) and antihypertensives were independently associated with the risk of dying in patients without DM. In DM group such independent association was confirmed for FPG and treatment of AH. We found a reduction in the risk of death for COVID-19 inpatients without DM, who received RAAS inhibitors compared with the corresponding risk of normotensive inpatients, who did not receive antihypertensives: OR 0.22 (95% CI 0.07-0.72) adjusted for age, gender and FPG. Conclusion: This result raises a question about the study of RAAS inhibitors effect in patients with Covid-19 without AH.

An umbrella review and meta-analysis of renin-angiotensin system drugs use and COVID-19 outcomes.

BACKGROUND: Despite the availability of extensive literature on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID-19-related outcomes by summarising the currently available evidence. METHODS: An umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19-related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random-effects modelling including several subgroup analyses. Heterogenicity was assessed using I2 statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines. RESULTS: Overall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75-0.86; I2  = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80-0.92; I2  = 43.9%), severe COVID-19 (OR = 0.86, 95%CI = 0.78-0.95; I2  = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04-1.46; I2  = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47-0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63-0.85). CONCLUSIONS: Collective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19.

Effects of angiotensin receptor blockers (ARBs) on clinical outcomes of patients with hypertension and COVID-19: A 7-month follow-up cohort study.

Introduction: Since the coronavirus disease 2019 (COVID-19) pandemic, the use of angiotensin II receptor blockers (ARBs) in hypertensive patients with COVID-19 has been controversial. Following our previous study, after one year, we intended to extend our sample size and results to investigate the effects of ARBs with both in-hospital outcomes and 7-month follow-up results in patients with COVID-19. Methods: Patients with a diagnosis of COVID-19 who were admitted to Sina Hospital, Tehran, Iran, from February to October 2020 participated in this follow-up cohort study. The COVID-19 diagnosis was based on a positive polymerase chain reaction test or chest computed tomography scan according to guidelines. Patients were followed for disease severity, incurring in-hospital mortality, complications, and 7-month all-cause mortality. Results: We evaluated 1413 patients with COVID-19 in this study. After excluding 124 patients, 1289 including 561(43.5%) hypertensive patients, entered the analysis. During the study, 875(67.9%) severe disease, 227(17.6%) in-hospital mortality, and 307(23.8%) 7-month all-cause mortality were observed. After adjusting for possible confounders, ARB was not associated with severity, in-hospital and 7-month all-cause mortality, and in-hospital complications except for acute kidney injury. Discontinuation of ARBs was significantly associated with higher in-hospital mortality and 7-month all-cause mortality (both P values<0.006). We observed a better 7-month outcome in those who continued their ARBs after discharge. Conclusion: The results of this study, along with the previous studies, provide reassurance that taking ARBs is not associated with the risk of mortality, complications, and poorer outcomes in hypertensive COVID-19 patients after adjustment for possible confounders.

The effect of renin-angiotensin-aldosterone system blockers on the course of COVID-19 in patients with arterial hypertension

Objective. To determine the presence or absence of the effect of therapy with renin-angiotensin-aldosterone system (RAAS) blockers in patients with COVID-19. Design and methods. We examined 57 patients who were treated in a medical unit at the FGAU CEC "Patriot" in the period from October to November 2020, with the diagnosis of "New coronavirus infection" and differed in the prescribed antihypertensive therapy. In group 1, drugs that affect the RAAS were used to treat hypertension before COVID-19 onset and during the treatment of COVID-19. In group 2, other drugs were used as the main antihypertensive agents before and during treatment for COVID-19. The severity of pneumonia in patients according to the results of computed tomography was 1-2. The patients were monitored for anthropometric indicators, body temperature, and laboratory data. Results. Groups 1 and 2 are comparable, differing only by height, but not by body mass index. The duration of treatment in group 2 was 1-2 days shorter than in group 1, but the result is not statistically significant due to the small sample. Thus, the hypothesis that differences between previous and ongoing antihypertensive therapy throughout the COVID-19 treatment period may affect the course and effectiveness of treatment has not been confirmed. Conclusions. Concomitant antihypertensive therapy with RAAS blockers does not alter the course of COVID-19 infection in patients. The duration of COVID-19 in patients receiving RAAS system blockers may be one day longer than for patients receiving other antihypertensive therapy. Copyright © 2021 All-Russian Public Organization Antihypertensive League. All rights reserved.

The Role of The Renin-Angiotensin System in The Pathogenesis of COVID-19

The angiotensin-converting enzyme docks onto the spike glycoprotein on the virion outward. The dimer of the enzyme{ACE}2 is an vital step in the mechanism of life-threatening acute respiratory failure. Human cells are infected with the syndrome coronavirus 2 (SARS-CoV-2).The systemic renin-angiotensin system stifles the expression of ACE2 (RAS) imbalance and advancement of multi-organ harm. In common, the RAS triggers vasoconstriction, hypertension, inflammation, fibrosis, and proliferation through the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and triggers the switch impacts through the ACE2/Ang (1-7)/Mas axis. The RAS may be triggered by chronic inflammation in hypertension, diabetes, heavy weight, and cancer. The ACE 2/Ang {1-7}/Mas axis is deactivated by means of SARSCoV-2-induced ACE2 internalization and shedding. As a result, we believe that two RAS hits are responsible for COVID-19 progression. In summary, the The ACE/Ang II/AT1R axis is triggered by chronic inflammation, which is the first hit. The second stems from the disruption of the ACE2/Ang (1-7)/Mas axis by COVID-19 infection. Furthermore, the two RAS hits might be the primary cause of elevated numbers of death in COVID-19 patients and comorbidities, and they might be used as a clinical target for COVID-19 therapy. © 2022 American Institute of Physics Inc.. All rights reserved.

Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England's prescription data during the COVID-19 pandemic (January 2019 to October 2020).

BACKGROUND: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. AIM: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. METHODS: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest. RESULTS: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. CONCLUSION: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.

Chapter 23 - Nasal and pulmonary routes of drug delivery

Nasal and pulmonary drug delivery are attractive routes for the administration of a growing number of drugs for topical and systemic treatment as well as for prevention by vaccines. This is of particular interest for drugs with poor bioavailability, as the gastrointestinal passage and hepatic first pass effect can be avoided. The development of drugs, vehicles, and devices made substantial progress. The drug delivery research is focused on transmucosal absorption enhancers such as surfactants, enzyme inhibitors, biopolymers, tight junction modulators, cyclodextrins, and gelling systems and on nasal and pulmonary carrier systems like nanoparticles, microspheres, nano- or microemulsions, and liposomes. Many approaches are still in early development and need further investigation. The trend for devices is going to nasal dry powder inhalers and smart pulmonary nebulizers. A new research area includes inhalable vaccines, biological drugs, and coronavirus treatments.

Charlson comorbidity index, neutrophil-to-lymphocyte ratio and undertreatment with renin-angiotensin-aldosterone system inhibitors predict in-hospital mortality of hospitalized COVID-19 patients during the omicron dominant period.

Purpose: To investigate the clinical predictors of in-hospital mortality in hospitalized patients with Coronavirus disease 2019 (COVID-19) infection during the Omicron period. Methods: All consecutive hospitalized laboratory-confirmed COVID-19 patients between January and May 2022 were retrospectively analyzed. All patients underwent accurate physical, laboratory, radiographic and echocardiographic examination. Primary endpoint was in-hospital mortality. Results: 74 consecutive COVID-19 patients (80.0 ± 12.6 yrs, 45.9% males) were included. Patients who died during hospitalization (27%) and those who were discharged alive (73%) were separately analyzed. Compared to patients discharged alive, those who died were significantly older, with higher comorbidity burden and greater prevalence of laboratory, radiographic and echographic signs of pulmonary and systemic congestion. Charlson comorbidity index (CCI) (OR 1.76, 95%CI 1.07-2.92), neutrophil-to-lymphocyte ratio (NLR) (OR 1.24, 95%CI 1.10-1.39) and absence of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) therapy (OR 0.01, 95%CI 0.00-0.22) independently predicted the primary endpoint. CCI ≥7 and NLR ≥9 were the best cut-off values for predicting mortality. The mortality risk for patients with CCI ≥7, NLR ≥9 and not in ACEI/ARBs therapy was high (86%); for patients with CCI <7, NLR ≥9, with (16.6%) or without (25%) ACEI/ARBs therapy was intermediate; for patients with CCI <7, NLR <9 and in ACEI/ARBs therapy was of 0%. Conclusions: High comorbidity burden, high levels of NLR and the undertreatment with ACEI/ARBs were the main prognostic indicators of in-hospital mortality. The risk stratification of COVID-19 patients at hospital admission would help the clinicians to take care of the high-risk patients and reduce the mortality.

Renin-Angiotensin System Inhibitors in Patients With COVID-19: A Meta-Analysis of Randomized Controlled Trials Led by the International Society of Hypertension.

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.

COVID-19 and chronic kidney disease: peculiarities of treatment

The present study aimed to characterize the management of patients with chronic kidney disease with concomitant COVID-19. Articles published in 2019-2021 in the PubMed, Scopus, and Google Scholar electronic databases were analyzed. As a result of this review, the following particularities of COVID-19 treatment in chronic kidney disease could be summarized. It is obligatory to continue treatment with renin-angiotensin-aldosterone system inhibitors in patients with chronic kidney disease and COVID-19. Lisinopril is considered used for avoiding the elevated renal expression of angiotensin-converting enzyme 2. Spironolactone can prevent acute lung injuries and is reasonable if the triple combination of drugs for reducing blood pressure is not effective. Low-dose rosuvastatin therapy is recommended for patients with COVID-19 and chronic kidney disease stages 3-5 treated with antiretroviral drugs such as lopinavir and ritonavir, remdesivir. Ezetimibe is reasonable to use in case of ineffective higher doses of statins and to decrease hospitalization risk. © Chernatska O., Grek A., 2022. All rights reserved